Process for the preparation of aminomethylene malononitrile

ABSTRACT

This invention is directed to a process for the preparation of aminomethylene malononitrile from dialkyl aminoacylonitrile including intermediates therein. Aminomethylene malononitrile is a known compound which is a valuable intermediate in the synthesis of thiamine.

United States Patent Leimgruber et a].

PROCESS FOR THE PREPARATION OF AMINOMETHYLENE MALONONITRILE Inventors: Willy Leimgruber, Montclair;

Manfred Weigele, North Caldwell,

both of NJ.

Assignee: Hoffmann-La Roche Inc., Nutley,

Filed: June 19, 1974 Appl. No.: 480,660

Related US. Application Data Division of Ser. No. 338,018, March 5, 1973, Pat.

No. 3,853,946, which is a division of Ser. No. 197,968, Nov. 11, 1971, Pat. No. 3,742,015, which is a division of Ser. No. 42,528, June 1, 1970, Pat. No. 3,655,716, which is a division of Ser. No. 719,834, April 9, 1968, Pat. No. 3,542,848.

US. Cl 260/4655 R Int. Cl. C07C 120/00; C07C 121/20 Field of Search 260/4655 R [4 1 Aug. 19, 1975 [56] References Cited Primary Examiner.loseph P. Brust Attorney, Agent, or FirmSamuel L. Welt; Jon S. Saxe; William H. Epstein 5 7 ABSTRACT This invention is directed to a process for the preparation of aminomethylene malononitrile from dialkyl aminoacylonitrile including intermediates therein. Aminomethylene malononitrile is a known compound which is a valuable intermediate in the synthesis of thiamine.

2 Claims, N0 Drawings PROCESS FORTHE PREPARATION OF AMINOMETHYLENE MALONONITRILE CROSS REFERENCE TO RELATED APPLICATIONS v This application is a divisional applicationof. Serial No. 338,01 8, filed March 5, 1973, now US. patent No. 3,853,946, issued Dec. 10, 1974. which inturn is a divisional application of Serial No. 197,968, filed November 11, 1971, now US. Patent 3,742,015, issued June 26, 1973, which in turn is a divisional application of our US. Patent Application Serial No. 42,528, filed June 1, 1970, now US. Patent No. 3,655,716, issued April 1 l 1972, which in turn is a divisional application of our US. patent application Serial No. 719,834, filed April 9, 1968, now US. patent No. 3,542,848, issued November 24, 1970.

BACKGROUND OF THE INVENTION The synthesis of thiamine has been described by a number of investigators such as Todd and Bergell in .lourn. Chem. Soc., pg. 364 (1937). In these syntheses a pyrimidine ring compound, i.e., 2-methyl-2-amino-5- bromomethylpyrimidine dihydro-bromide and a thiazole ring compound, i.e., 4-methyl-5-B-hydroxyethyl thiazide are condensed to form the thiamine ring struc ture. This pyrimidine compound is prepared from 2- methyl-4-amino-5-cyanopyrimidine which is formed by the condensation of aminomethylene malononitrile with acetimino ethyl ether, as described in Chapter 16 of the Vitamins, Chemistry, Physiology, Pathology, Vol. III, Sebrell and Harris, Academic Press. lnc., New

York (1954).

This procedure therefore depends on the use of the aminomethylene malononitrile which has been a difficult material to synthesize economically. In view of this fact, it has long been desired to provide an economical means of synthesizing aminomethylene malononitrile utilizing inexpensive and readily available starting materials.

SUMMARY OF THE INVENTION In accordance with this invention, it has been found that aminomethylene malononitrile, which has the for- H N CH==C can be synthesized economically from a dialkyl aminoacrylonitrile of the formula:

\-N-- CHICK-JUN formulall above, an acetal compound of the formula:

III

' wherein R and R5 are as above, and R is lower alkyl,

N- CH2CH2 GEN IV wherein R and R are as above, is treated with a hydrogen acceptor at a temperature of at least 50C. in the presence of a dehydrogenation catalyst.

DETAILED DESCRIPTION As used throughout the specification, the term lower alkyl includes both straight and branched chain alkyl groups containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, and the like. As used throughout the specification, the term lower alkanoyl includes alkanoyl groups containing from 2 to 6 carbon atoms such as acetyl, propionyl, and butyryl.

The reaction of acetontrile with the acetal of formula III to form the compound of formula II is'carried out at. a temperature of at least C. Generally, it is preferred to utilize a temperature of from C. to 250C. in carrying out this reaction. While this reaction can be carried out at atmospheric pressure, superatmospheric pressures are utilizedwhen higher temperatures are utilized. This reaction can be carried out without the need for utilizing any solvent. However, if desired, an inert organic solvent can be utilized. Any conventional inert organic solvent such as benzene, toluene, methylene chloride, can, if desired be utilized in carrying out this reaction.

The second method of preparing the compound of formula 11 above is by treating a compound of formula IV above with a hydrogen acceptor at a temperature of at least 50C. in the presence of a dehydrogenation catalyst. Any conventional dehydrogenation catalyst can be utilized in carrying out this reaction. Among the preferred dehydrogenation catalysts which can be utilized in this reaction are palladium, Raney nickel and cupric chromite. In carrying out this reaction, any conventional hydrogen acceptor can be utilized. Among the preferred hydrogen acceptors is oxygen which can be supplied by carrying out the reaction in the presence of air. Alternatively, the oxygen can be supplied in the form of bottled oxygen. Other hydrogen acceptors which can be advantageously utilized in this process are aliphatic ethers containing at least one ethylenic moiety bound to the oxygen atom and having from 3 to 15 .carbon atoms such as methyl vinyl ether and cyclic ethers such as dihydropyran.

lnconvening the compound of formula 'IV above to the compound of formula 11 above, no solvent need be present. Generally, in carrying out this reaction, av temperature of at least 50C. should be utilized with temperatures of between 80C. to 200C, being preferred. If high temperatures are utilized, the reaction may be carried out under superatmospheric pressure.

In accordance with this invention, the compound of formula I above is synthesized from the compound of formula ll above by means of the following reaction scheme:

ratio in 'carrying out the reaction of step (a). In carrying out the reaction of step- (a), temperatures of from about l0C. to +lOC. should be utilized. Generally, it is preferred to carry out the reaction of step (a) in the presence of an inert'organic solvent. Any conventional inert organic solvent can be utilized. However, the preferred solvents are the halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, etc. In carrying out this reaction, any of the lower alkyl u N Ra WCN II II]. N 3

N G)- a Y Rz R4 v l? V .'.l

, R "'cN v1 IX R VI\CHO ry 2 W e (s) weca I R .cn

. N-OSO H v 3 VII CN 2 i it? i N (9 7 l; /\NR6 Z9 Ji i 'R/ 0N en H2N l wherein R and R are as above, R R

R R and R, are lower alkyl, Y is a halide ion. and R is lower alkanoyl, and

Z is the CH -,OSO ion.

The conversion of compounds of the formula ll above to compounds of the formula Vabovc is carried out, as in reaction step (a), by treating the compound of the formula ll above with a diloweralkyl formamide in the presence of an inorganic acid halide condensing agent. These three reactants may be used in any molar formamidcs, preferably dimethyl formamide can be utilized. Among the preferred inorganic acid halide condensing agents which can be utilized in accordance with this invention are included phosphorous oxychloride, phosgcnc, 'thionyl chloride, phosphorous pentachloride, etc.

The compound of formula V above is converted into the compound of formula VI above, as in reaction step (b). by raising the pH of an aqueous solution containing the compound of formula V above to a value of from 7 to 9. This is accomplished by treating the compound of formula V above with an aqueous alkaline medium sufficient to raise the pH to a range'of from 7 to 9. Any conventional inorganic base such as sodium hydroxide, potassium hydroxide, etc. can be utilized as the alkaline medium to provide a pH within the range of from about 7 to 9. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. If desired, elevated or reduced temperatures can be utilized.

The compound of formula VI above is converted to the compound of formula VII-A above, via reaction step (c,), by means of reacting the compound of the formula VI above with a compound of the formula:

NH2OR wherein R is as above.

In the reaction of step (0,), the two reactants may be used in any molar ratio. The reaction of step (c,) is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. Among the inert organic solvents that can be utilized are included halogenated hydrocarbons such as chloroform, dichloromethane, l,2-dichloroethane, etc. Generally, in carrying out this reaction, room temperature ,is utilized. During the reaction of step (c the temperature utilized should not be above 30C. It is preferred to carry out this reaction at a temperature of from about 0C. to C.

The compound of formula VII-A can be converted to the compound of formula VIII via reaction step (d,) by heating the compound of formula VIIA to a temperature of from 70C. to 90C. The reaction of step (d,) is carried out in the presence of an inert organic solvent. Any of the solvents'hereinbefore mentioned in connection with reaction step (c can be utilized in carrying out the reaction of step (d The compound of formula VI above can be converted to the compound of formula VII, via reaction step (c) by means of reacting the compound of the formula VI with a compound of the formula:

XI-A

This reaction is preferably carried out by suspending the two reactants in water and allowing the reaction to proceed at room temperature. During the reaction of step (c), the temperature utilized should not exceed about C. Generally, it is preferred to utilize a temperature of from 0C. to 25C. in this reaction.

The compound of formula VII above can be converted to the compound of formula VIII, as in reaction step (d) by adjusting the pH of the aqueous reaction mixture containing the compound of formula VI] to about 5.5 to 8.5 and warming the reaction mixture to a temperature of from about 60C. to 90C. The pH of the reaction mixture is adjusted to a range of 5.5 to 8.5 by treating the aqueous mixture with an alkali such as an alkali metal hydroxide. Among the preferred alkali are included sodium hydroxideppotassium hydroxide, etc.

The conversion of compounds of the formula VI above to the compound of the formula IX above is carried out, as in're'action step (f), by treating the com- I pound of the formula VI above with a hydrazine of the formula:

wherein R., and R are as above. In carrying out the reaction of step (f) any mole ratio of the reactants can be utilized. Generally, this reaction is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized. Among the preferred solvents are included the lower alkanols, such as methanol, ethanol, etc. In carrying out this reaction, temperature and pressure are not critical and this reac tion can be carried out at room temperature and atmospheric pressure. However, it is preferred to carry out this reaction at the reflux temperature of the solvent. Therefore, temperatures of from 50C. to C. are generally utilized, depending upon the reflux temperature of the solvent.

The conversion of compounds of the formula IX above to the compounds of the formula X above, via reaction step (g), is carried out by treating the compound of the formula IX above with a dilowcr alkyl sulfate. Generally, this reaction is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized in carrying out this reaction. Among the conventional inert organic solvents which can be utilized are included lower alkanols, such as methanol or ethanol. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure or at elevated temperatures. Generally, it is preferred to carry out this reaction at the reflux temperature of the solvent.

The compound of formula X is converted to the compound of formula VIII via reaction step (h) by treating the compound of formula X above with an alkali. Any conventional alkali such as an alkali metal hydroxide or an alkali metal lower alkoxide, can be utilized in carrying out this reaction. Among the preferred alkali are included sodium hydroxide, potassium hydroxide, sodium methoxide, etc. This reaction is carried out in the presence of an inert organic solvent. Among the solvents that can be utilized are the lower alkanols, such as methanol or ethanol. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and at atmospheric pressure. If desired, elevated temperatures such as 80C. can be utilized in carrying out this reaction.

The compound of formula VIII above is converted into the compound of formula I above by treating the compound of formula VIII above, as in reaction step (c), with liquid ammonia. This reaction is generally carried out a temperature of from minus 70C. or below. It is preferred to carry out this reaction at a temperature of from minus 70C. to minus C. This reaction is carried out by dissolving the compound of formula VIII above in liquid ammonia. After the compound of formula VIII is dissolved in liquid ammonia, the resulting solution is slowly warmed to room temperature so as to produce the compound of formula 1 above. This warming should take place within a period of time of at least one hour. Generally, it is preferred to carry out this warming step within a period of from 4 to 24 hours.

Another means of converting the compound of formula Vlll above into the compound of the formula 1 above is by treating the compound of the formula Vlll above with a saturated aqueous solution of ammonia hydroxide. This reaction is carried out in an aqueous medium and by heating the aqueous mixture containing the compound of formula V111 and ammonium hydroxide to a temperature of from about 80C. to 100C.

This invention will be more fully understood from the specific examples which follow. These examples are intended to illustrate the invention and are not to be construed as limitative thereof. All temperatures are in degrees Centigrade.

EXAMPLE 1 Dehydrogenation of dimethylaminopropionitrile to dimethylaminoacrylonitrile The catalytic dehydrogenation of dimethylaminopropionitrile was carried out under the following conditions:

1n the above reaction, a reaction mixture was prepared containing the catalyst and dimethylaminopropionitrile. Where an ether hydrogen acceptor was utilized, the hydrogen acceptor was present in a molar amount of ten times the moles of dimethylaminopropionitrile in the reaction mixture and the reaction was carried out under nitrogen. In the cases where air was used, the reaction was carried out by exposing the reaction mixture to the atmosphere. The catalyst was present in an amount of about by weight or 30% by weight based upon the weight of the dimethylaminopropionitrile as indicated above. The final product obtained by vapor phase chromatography was dimethylaminoacrylonitrile. This product distilled at l C. at 3mm Hg.

EXAMPLE 2 Preparation of 3-dimethylaminoacrylonitrile 173.0 g. of the diethylacetal of dimethylformamide l .18 moles) and 400 ml. of acetonitrile were placed in a 1200 ml. autoclave. Air was removed from the autoclave by flushing with nitrogen, and after purging charged to 50 p.s.i. with nitrogen. The reaction was carried out for 36 hours at 150C. Upon completion of the reaction, excess acetonitrile was removed by vacuum distillation using a rotary evaporator at a vacuum of 135 mm Hg. and a waterbath temperature of 60C.

maximum. The remaining residue was fractionated using a 24 inch Vigreaux column. After discarding a small first fraction, the material boiling at 115C. and 3.0 7 mm Hg was collected. This material was 3- dimethylaminoacrylonitrile.

EXAMPLE 3 Preparation of (3dimethylamino-2-cyano-2-propenl ylidene )dimethylammonium perchlorate 10 ml. of N,N-dimethylformamide were stirred at 4 to 7 and 10 ml. of phosphoroxy chloride were added dropwise in such a rate as to maintain the reaction temperature below 0. The resulting semi-solid reaction mixture was diluted with ml. of 1,2-diehloroethane. On warming to room temperature, a clear amber solution was obtained. The solution was cooled to -8 to l 0C. and 5.91 g. of 3dimethylamino-acrylonitrile, dissolved in 15 ml. of 1,2-dichl0roethane were added dropwise with stirring within 15 minutes. After removal of the solvent in vacuo a semi-crystalline residue was obtained. The material was dissolved in 20 g. of ice/water and 8.1 g. of sodium perchlorate were added to this solution. On cooling (3dimethylamino-Z-eyano-2- propen-l-ylidene)-dimethylammonium perchlorate as crystals, (m.p. 139-l42) was obtained.

EXAMPLE 4 Preparation of 2-eyano-3dimethylaminoacrolein 36 ml. (0.465 mole) of N,N-dimethylformamide were stirred at 0 and 36 ml. (0.392 mole) of phosphorus oxychloride were added dropwise (a salt/ice bath was used in order to keep the reaction mixture at 0). To the stirring semi-solid, faintly colored reaction mixture was added 300 ml. of 1,2-dichloroethane. Upon warming to room temperature by means of a water bath (25), a clear solution resulted which was cooled to 7 with an ice-salt bath. A solution of 30 ml. (0.293 mole) of B-dimethylaminoacrylonitrile in ml. of 1,2- dichloroethane was added dropwise keeping the tem' perature between 4 to 7. The addition required about 1 hour. The cooling bath was removed and the clear amber reaction mixture allowed to come to room temperature. The reaction mixture was transferred to a 2 liter, round bottomed flask and the solvent removed in vacuo leaving a semi-solid orange colored residue. A g. of ice was added to the residue which gradually dissolved with evolution of heat. The solution was transferred to a beaker and the pH adjusted to 8.4 by adding carefully 2N sodium hydroxide (815 ml. were required) to the stirred solution at 1520. The resulting solution was extracted with ethyl acetate in a liquidliquid extractor overnight. The ethyl acetate extract was cooled, the crystals which had separated were filtered off, washed with cold ethyl acetate and dried in vacuo, affording crude 2-cyano-3- dimethylaminoacrolein, as deep yellow prisms, m.p. l43-l44. This material was dissolved in 500 ml. of hot water, treated with 2 g. of norite, the solvent removed in vacuo and the residue crystallized from absolute ethanol, producing the pure product in the form of light yellow prisms. m.p. l43144.

EXAMPLE 5 Preparation of 2-cyano-3dimethylaminoacrolein Into a 250 ml. 3-neck-round-bottom flask were placed 7.3 g. (0.1m) of dimethylformamide and ml. dichloromethane. The stirred solution was cooled in ice/water and phosgene was bubbled through for 30 minutes. A white solidformed. The solvent was removed in vacuo. The remaining solid was suspended in 120 ml. dichloromethane. Thestirred suspension was cooled in an ice/salt bath to lC. A solution of 9.6 g. (0.1m) 3-dimethylaminoacr-ylonitrile in 40 ml. of dichloromethane was added dropwise, maintaining the temperature below 0C. After completed addition a clear yellow solution resulted. The solutionwas evaporated in vacuo to dryness. The solid residue was dissolved in 20 ml. of water. The aqueous solution was cooled to 0C. and adjusted to pH 8.5 with N sodium hydroxide solution. The alkaline solution was allowed to stand at room temperature for 4 hours, during which time a crystalline solid precipitated. The whole mixture was extracted with 5 X 100 ml. of dichloromethane. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness in vacuo. The crystalline residue consisted of 2-cyano-3- dimethylaminoacrolein, m.p. l40-l4l. After recrystallization from ethanol, the melting point was 142143.5.

EXAMPLE6 Preparation of dimethylaminomethylenemalononitrile To a mixture of g. of 2-cyano-3- dimethylaminoacrolein and 100 ml. of ethylene chloride was added in small portions with stirring 9 g. of 0-acetylhydroxylamine hydrochloride. The mixture was stirred at room temperature for minutes and then heated at reflux temperature for 1 hour. On cooling, dimethylaminomethylenemalononitrile crystallized from the reaction solution, and was collected by filtration (m.p. 8l82).

EXAMPLE 7 Preparation of N-( 3-dimethylamino-2-cyano-2- propenel -ylidene )-N,N'-dimethylhydrazine hydrochloride A solution of 12.4 g. of 2-cyano-3- dimethylaminoacrolein and 9.6 g. of 1,1-dimethylhydrazine hydrochloride in 50 ml. of methanol was heated to reflux temperature for 90 minutes. On cooling the reaction mixture a first crop of N-(3- dimethylamino-2-cyano-2-propenel -ylidene )-N ',N dimethylhydrazine hydrochloride (m.p. 173) precipitated in crystalline form and was filtered off. A second crop (m.p. l70l72) was obtained from the mother liquor on concentrating.

EXAMPLE 8 Preparation of N-( 3-dimethylamino-2-cyano-2- propene-l-ylidene)-N',N'-dimethylhydrazine 5- g. of the N-(3-dimethylamino-2-cyano-2-propenel-ylidene )-N,N'-dimethylhydrazine hydrochloride was dissolved in the minimum required amount of water. The pH was adjusted to 8 by addition of 10% sodium hydroxide solution. The desired product N-(3- dimethylamino-2-cyano-2-propenel -ylidene )-N,N dimethylhydrazine precipitated and was filtered off (m.p. |3()-l34).

EXAMPLE 9 Preparation of N-( 3-dimethylamino-2-cyano-2-propen' l-ylidcne)-N'.N.N-trimethylhydrazinium methyl sulfate 3.3 g. of N-(3-dimethylamino-2-cyano-2-propen-l- 10 ylidene)-N',N-dimethylhydrazine were dissolved in 20 ml. of absolute ethanolvThe solution was heated on a steambath. and 1.9 ml.of dimethyl sulfate was added. The resulting mixture was allowed to cool to room temperatureand was then refrigerated. The product N-(3- dimethylamino-2-cyano-2-propenl -ylidene )N ,N ,N'-

'trimethylhydrazinium methyl sulfate was collected by filtration (m.p. l47l49).

EXAMPLE 10 EXAMPLE 11 Preparation of dimethylaminomethylenemalononitrile To a slurry of 12.4 g. of 2-cyano-3- dimethylaminoacrolein in 50 ml. of water was added in small portions 13.6 g. of hydroxylamino-O-sulfonic acid (91% pure). The resulting clear solution was stirred for an additional 10 minutes, then cooled to 0 and adjusted to pH 6.0 by addition of approximately 26 ml. of 5N sodium hydroxide solution. The mixture was heated for 20 minutes in a water bath at A pH 3 was maintained over this period by dropwise addition of 5N sodium hydroxide solution. After cooling to room temperature, the mixture was extracted with 3 X ml. of methylene chloride. The combined extracts were washed with 50 ml. of water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Thus, dimethylaminomethylenemalononitrile was obtained. After recrystallization from isopropanol, the material had a melting point of 9395.

EXAMPLE 12 Preparation of dimethylaminomethylenemalononitrile from 3dimethylaminoacrylonitrile Into a 250 ml. 3-neck-round-bottom flask are placed 7.3 g. (0.1m) of dimethylformamide and 150 ml. of dichloromethane. The stirred solution is cooled in ice/- water and phosgene is bubbled through for 30 minutes. A white solid forms. The solvent is removed under reduced pressure. The remaining solid is suspended in ml. of dichloromethane. The stirred suspension is cooled in an ice/salt bath to 10. A solution of 9.6 g. (0.1m) of 3-dimethylaminoacrylonitrile in 40 ml. of dichloromethane is added dropwise, maintaining the temperature below 0. After completed addition a clear yellow solution results. The solution is evaporated to dryness under reduced pressure. The remaining yellow solid is dissolved in 20 ml. of water. The aqueous solution is cooled to 0 and adjusted to pH 8 with 5N sodium hydroxide (-15 ml.). The alkaline solution is allowed to stand at room temperature for 90 minutes. A crystalline solid precipitates. The slurry is diluted with 20 ml. of water, and, while stirring 12.5 g. (0.1m) of hydroxylamino-O-sulfonic acid (91-93% pure) is added as a solid. A clear solution results. After 10 minutes stirring at room temperature, the solution is cooled in ice/water and the pH is adjusted to 7 with N sodium hydroxide (-26 ml.). The neutral solution is heated briefly to 75 (-3-4 min.). On cooling the main fraction of dimethylaminomethylenemalononitrile precipitates in crystalline form. The aqueous mother liquor is readjusted to pH 7 and extracted with 3 X 100 ml. of dichloromethane. The combined organic extracts are dried over magnesium sulfate and evaporated to dryness. The residue is dissolved in 50 ml. of isopropanol. The resulting solution is treated with activated charcoal and filtered hot. On concentration of the solution an additional crop of dimethylaminomethylencmalononitrile is obtained.

EXAMPLE 14 wherein R and R are lower alkyl containing from 1 to 6 carbon atoms; comprising dissolving said dinitrile in liquid ammonia at a temperature below about C. to form a reaction mixture and thereafter bringing said reaction mixture to room temperature within a period of at least one hour to form aminomethylene malonitrilc.

2. A process for producing aminomethylene malonitrile from a dinitrile of the formula:

said malonitrile. 

1. A PROCESS OF PRODUCING AMINOMETHYLENE MALONITRILE FROM A DINITRILE COMPOUND OF THE FORMULA:
 2. A process for producing aminomethylene malonitrile from a dinitrile of the formula: 